There are few long term prospective population-based studies of sex differences in rates, determinants, and consequences of bone loss, kyphosis, declining bone strength, and fracture. The 20 year Rancho Bernardo Study (RBS) of osteoporosis has repeated measures of 7 primary outcomes: bone mineral density (BMD), clinical and morphometric fractures, kyphosis, bone and muscle strength, functional imitations, and morbidity and mortality. Major exposure variables include changes in lifestyle, weight, sex hormones, and NTx (a bone resorption marker), as well as baseline measures of adipocytokines, nflammatory markers, OPG, RANKL, vitamin D and PTH, IGF-1, 28 candidate osteoporosis genes, and medical and medication history. We propose a final clinical evaluation for surviving members of our elderly cohort. Our longitudinal data will permit comparison of antecedent characteristics of participants and non- participants, to determine the potential impact of survivor and participant bias on study assumptions. We will re-examine 300-350 men and 500-550 women from the ~1000 RBS men and womenwho remain local, ambulatory, community-dwelling, and who had at least 3 previous DXA scans. This new evaluation is expected to increase by 70% the number of RBS participants with 5 or more DXA scans of BMD since 1988, double the number of morphometric spine fractures, increase by 150 the number of validated clinical fractures, and increase from 2 to 3 the number of repeated measures of kyphosis and bone strength. At this final visit we will add to the clinic evaluation, for the first time, peripheral computed tomography (pQCT) to complement our studies of bone strength and geometry, and electron beam computed tomography (EBCT) which provides a quantitative measure of coronary artery calcium. Our main goal remains the study of sex differences in bone outcomes. We are drawn to the possibility of a central role for endogenous sex hormones based, in part, on our Osteo IV analyses showing striking sex differences in the association of inflammatory markers, adipocytokines, ghrelin, OPG, insulin and IL6 with bone density, and on the gender paradox of a universal and presumably intrinsic 10-15 year earlier clinical manifestation of heart disease in men than women, and the converse 10-15 year earlier manifestation of bone disease in women. Clinical disease is paralleled by calcium gain in arteries and calcium loss in bone. Our proposed study of bone and coronary calcium offers an additional model for our investigations of the biological basis for sex differences in calcium regulation. Our goal is to develop a coherent picture of the interactive effects of sex hormones and lifestyle, biomarkers, vitamin D, PTH, and genes on each bone outcome.